E DI TO R IA L
BJD
British Journal of Dermatology
Prospective registration of clinical trials published in the British Journal of Dermatology
DOI: 10.1111/bjd.13314
So far so good? Readers of the BJD will know that reports of randomized controlled clinical trials (RCTs) are a core component of the journal’s content. Indeed, high-quality reports of RCTs are at the heart of the journal’s aim to publish the highest-quality dermatology research.1 A recent editorial by Williams2 highlighted the journal’s long history of publishing high-quality, highly cited trials.3,4 One of this editorial’s authors (J.B.) is Clinical Trials Section Editor for the BJD. This role involves reviewing all RCTs submitted to the journal and ensuring they are reported in a clear and transparent manner. In order to encourage this, the journal requests that all submissions of RCTs include a completed CONSORT checklist (www.consort-statement.org). We aim for the RCTs published in the BJD to be reported clearly enough for readers to be able to make their own judgements of their quality and validity. So far, so good. But does this mean that the BJD has its house fully in order with respect to the RCTs it publishes? Well, not quite. There are two sources of bias in RCT reporting that can have a detrimental impact on the scientific record, and the BJD needs to play its part in avoiding them. The first of these is publication bias. Instead of considering only the RCTs that are published, it is also worth considering those that never see the light of day. It is a well-known fact that as many as 50% of trials never get published.5,6 This ‘publication bias’ may exist because the trialists decide that it is not worth trying to publish their results if they do not identify an exciting new treatment that is going to transform care. Journals are also guilty of tending to be more interested in studies that show ‘positive’ findings;7 this has been demonstrated in the dermatology literature.8
So what? Having RCTs out in the unpublished ‘ether’ gives an inaccurate view of which treatments have been assessed, and trials may end up being duplicated. This research waste is a poor use of limited resources and something that cannot be continued in the context of ever-tightening healthcare research budgets.9 Clinical trial data must be available in their entirety in order to allow guideline developers and healthcare policy makers to make appropriate decisions. If negative or less
© 2014 British Association of Dermatologists
favourable results of studies are not presented, this usually leads to an overestimate of the effect of an intervention. If the balance of the beneficial and unbeneficial effects (harms or inefficacy) is more in the direction of unbeneficial (negative results), healthcare will be improved if it is clearly reported that the treatment being investigated was not beneficial and probably should not be used in future practice. Furthermore, participants in a clinical trial expect that the data will improve healthcare, and not publishing is unethical, because patients give informed consent on the assumption that data will inform healthcare decisions. The second source of bias to consider is selective reporting of outcomes. Even if an RCT is published, can we be sure that the trialists really did what they said they would do when they set off on the long journey from trial protocol to published report? Although some changes may be inevitable, it is essential that any changes from the original plan (the trial protocol) are reported transparently, allowing others to make their own judgement of the possible impact of these changes on the trial’s validity. If a trial proposes to assess a number of outcomes, but only some are included in the final published report, is this because only the ‘positive’ outcomes were reported? Selective reporting of positive outcomes has been demonstrated in both the general medical and dermatology literature.8,10,11
So what can be done about this? BJD readers will be aware that trial registration has recently been debated in the European Parliament. After much pressure by groups such as the AllTrials campaign, Members of the European Parliament voted by a huge majority to adopt a new Clinical Trials Regulation from 2016.12,13 The new regulation will, among other things, require that all drug trials in Europe are registered before they begin [on the publicly accessible European Union (EU) Clinical Trials Register], and that a summary of the results from each trial is published on the register within a year of the trial’s end. Previous attempts to encourage clinical trial registration have lacked any ‘teeth’, but there are possible financial penalties for trialists who do not adhere to the new rules. While these will apply only to trials that have not yet started, it is certainly a positive step towards greater clinical trial transparency. Mandatory registration of all trials will help to reduce the impact of publication bias and selective reporting of outcomes. The next step will be to encourage full access to trial protocols as well.14
British Journal of Dermatology (2014) 171, pp681–683
681
682 Editorial
And what about randomized controlled trials published in the BJD? Although the BJD has supported the concept of trial registration since 2005,15 it has not insisted on mandatory trial registration in the manner of some high-impact journals.16 However, it would appear that the future direction of travel, in the EU at least, is towards mandatory registration of trials. While we acknowledge that the RCTs published in the BJD are often carried out in countries outside the EU, we believe that the positive impact of a policy of mandatory prospective trial registration (regardless of where the trials are carried out) merits adoption by the journal. Looking at recent submissions, trial registration is clearly not an alien concept to the authors submitting RCTs for publication to the BJD; approximately two-thirds of the RCTs submitted in the period of 2011–13 were registered. Although many of these were large RCTs produced with industry support (where familiarity with trial registration might be expected), many RCTs produced by independent researchers were also registered. However, due to the long timescales involved in designing and carrying out trials, it seems reasonable to allow an ‘amnesty’ period, after which trial registration will become mandatory for all RCTs submitted to the journal.
Which registry and when? We would expect all RCTs carried out in the EU to be registered on the EU Clinical Trials Register (www.clinicaltrials register.eu). RCTs carried out in any other country can be registered on any publicly accessible registry. Observational studies need not necessarily be registered but it is possible to do so. A large proportion of RCTs are registered on the Clinicaltrials.gov website (www.clinicaltrials.gov) or the Current Controlled Trials register (www.controlled-trials.com); this can be done free of charge or for a small fee. Many countries or regions have such registries already, such as the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) and the Netherlands Trial Register (www.trialregister.nl). The World Health Organization (WHO) has a list of primary registries in the WHO Registry Network (www.who.int/ictrp/ network/primary/en/), which meet specific criteria for content, quality and validity, accessibility, unique identification, technical capacity and administration. A registration number will be granted on registration; this can be included when the publication is sent to a scientific journal. The registry used by authors must be publicly accessible; internal registries that can be accessed only by specific employees of an organization are not acceptable. Stating other reference numbers, such as an ethical review board reference number (as has occurred with previous submissions to the BJD) is not an acceptable alternative. Registration must be prospective, not retrospective. This should be before any participants are recruited, although some registries do allow trials to be registered within a specified British Journal of Dermatology (2014) 171, pp681–683
time window after the first participant has been recruited. Registration of the trial after it has been completed (retrospective registration) is not acceptable. Authors of RCTs submitted to the BJD still sometimes give lack of awareness of trial registries as a reason for not registering their trial, but this no longer seems a reasonable excuse.
Protocols, interventions and outcome measures We would also like to draw trial authors’ attention to two other helpful resources: SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and TIDieR (Template for Intervention Description and Replication). The protocol of a clinical trial is essential for study conduct, review, reporting and interpretation. SPIRIT is an international initiative that aims to improve the quality of clinical trial protocols by defining an evidence-based set of items to address when preparing a protocol (www.spirit-statement.org). Once it has been prepared, the protocol should be made publicly available, either through publication or registration on a suitable registry. The quality of description of interventions in trial publications is often surprisingly poor. With a complete published description of interventions, clinicians and patients can reliably implement interventions that are shown to be useful, and other researchers can replicate or build on research findings. The TIDieR checklist and guide are useful resources to support the adequate description of trial interventions.17 A final point: there is considerable heterogeneity in the outcome measures (also called outcome domains or constructs) and outcome measurement instruments used in clinical trials. Recent efforts to harmonize outcome measures and instruments by developing core outcome sets (www.comet-initia tive.org; and for dermatology www.homeforeczema.org), and efforts to improve the quality of outcome measurement instruments (www.cosmin.nl) will lead to research of greater quality and validity. Trialists should be aware of these initiatives and should aim to include the recommended outcome measures in their trials.
A call to authors submitting clinical trial manuscripts to the BJD The WHO states that, ‘the registration of all interventional trials is a scientific, ethical and moral responsibility’. So, we encourage all authors planning to submit RCT reports to the BJD to register the trial prospectively and then report the trial clearly and transparently, following the CONSORT reporting guidelines. We also hereby give notice of an amnesty period, lasting until 1 October 2015, after which any RCT submitted to the BJD must be prospectively registered on a trial registry. We look forward to receiving and publishing many more high-quality, prospectively registered, transparently reported RCTs in the BJD in the coming years. © 2014 British Association of Dermatologists
Editorial
Conflicts of interest The authors are section editors for the British Journal of Dermatology, and coedit the ‘Putting Papers into Practice’ section of the journal. 1
Centre of Evidence Based Dermatology, King’s Meadow Campus, University of Nottingham, Lenton Lane, Nottingham, NG7 2NR, U.K. 2 Department of Dermatology, Academic Medical Center, University of Amsterdam, A0-227, PO Box 22700, 1100 DD, Amsterdam, The Netherlands E-mail: [email protected]
J. BATCHELOR1 P.I. SPULS2
References 1 Anstey A. The British Journal of Dermatology: 125 years, 28 editors, enduring values. Br J Dermatol 2013; 169:238. 2 Williams H. The outstanding record of clinical trials in the British Journal of Dermatology. Br J Dermatol 2014; 170:761–3. 3 Saurat JH, Stingl G, Dubertret L et al. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol 2008; 158:558–66. 4 Ruzicka T, Lynde CW, Jemec GB et al. Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebo-controlled, multicentre trial. Br J Dermatol 2008; 158:808–17.
© 2014 British Association of Dermatologists
683
5 Simes RJ. Publication bias: the case for an international registry of clinical trials. J Clin Oncol 1986; 4:1529–41. 6 Dickersin K, Rennie D. Registering clinical trials. JAMA 2003; 290:516–23. 7 Dwan K, Gamble C, Williamson PR et al. Systematic review of the empirical evidence of study publication bias and outcome reporting bias – an updated review. PLoS ONE 2013; 8:e66844. 8 Nankervis H, Baibergenova A, Williams HC, Thomas KS. Prospective registration and outcome-reporting bias in randomized controlled trials of eczema treatments: a systematic review. J Invest Dermatol 2012; 132:2727–34. 9 Chalmers I, Glasziou P. Avoidable waste in the production and reporting of research evidence. Lancet 2009; 374:86–9. 10 Mathieu S, Boutron I, Moher D et al. Comparison of registered and published primary outcomes in randomized controlled trials. JAMA 2009; 302:977–84. 11 Bourgeois FT, Murthy S, Mandl KD. Outcome reporting among drug trials registered in ClinicalTrials.gov. Ann Intern Med 2010; 153:158–66. 12 AllTrials. Europe votes for clinical trial transparency. Available at: http://www.alltrials.net/2014/europe-votes-for-clinical-trial-trans parency (last accessed 30 July 2014). 13 Goldacre B. Improving, and auditing, access to clinical trial results. BMJ 2014; 448:g213. 14 Chan A-W. Bias, spin, and misreporting: time for full access to trial protocols and results. PLoS Med 2008; 5:e230. 15 Ormerod AD, Williams HC. Compulsory registration of trials. Br J Dermatol 2005; 152:859–60. 16 Williams HC, Goldsmith L. The JID opens its doors to high quality randomised controlled clinical trials. J Invest Dermatol 2006; 126:1683–4. 17 Hoffman TC, Glasziou PP, Boutron I et al. Better reporting of interventions: template for intervention description and replication (TIDieR) checklist and guide. BMJ 2014; 348:g1687.
British Journal of Dermatology (2014) 171, pp681–683
BJD
British Journal of Dermatology
Prospective registration of clinical trials published in the British Journal of Dermatology
DOI: 10.1111/bjd.13314
So far so good? Readers of the BJD will know that reports of randomized controlled clinical trials (RCTs) are a core component of the journal’s content. Indeed, high-quality reports of RCTs are at the heart of the journal’s aim to publish the highest-quality dermatology research.1 A recent editorial by Williams2 highlighted the journal’s long history of publishing high-quality, highly cited trials.3,4 One of this editorial’s authors (J.B.) is Clinical Trials Section Editor for the BJD. This role involves reviewing all RCTs submitted to the journal and ensuring they are reported in a clear and transparent manner. In order to encourage this, the journal requests that all submissions of RCTs include a completed CONSORT checklist (www.consort-statement.org). We aim for the RCTs published in the BJD to be reported clearly enough for readers to be able to make their own judgements of their quality and validity. So far, so good. But does this mean that the BJD has its house fully in order with respect to the RCTs it publishes? Well, not quite. There are two sources of bias in RCT reporting that can have a detrimental impact on the scientific record, and the BJD needs to play its part in avoiding them. The first of these is publication bias. Instead of considering only the RCTs that are published, it is also worth considering those that never see the light of day. It is a well-known fact that as many as 50% of trials never get published.5,6 This ‘publication bias’ may exist because the trialists decide that it is not worth trying to publish their results if they do not identify an exciting new treatment that is going to transform care. Journals are also guilty of tending to be more interested in studies that show ‘positive’ findings;7 this has been demonstrated in the dermatology literature.8
So what? Having RCTs out in the unpublished ‘ether’ gives an inaccurate view of which treatments have been assessed, and trials may end up being duplicated. This research waste is a poor use of limited resources and something that cannot be continued in the context of ever-tightening healthcare research budgets.9 Clinical trial data must be available in their entirety in order to allow guideline developers and healthcare policy makers to make appropriate decisions. If negative or less
© 2014 British Association of Dermatologists
favourable results of studies are not presented, this usually leads to an overestimate of the effect of an intervention. If the balance of the beneficial and unbeneficial effects (harms or inefficacy) is more in the direction of unbeneficial (negative results), healthcare will be improved if it is clearly reported that the treatment being investigated was not beneficial and probably should not be used in future practice. Furthermore, participants in a clinical trial expect that the data will improve healthcare, and not publishing is unethical, because patients give informed consent on the assumption that data will inform healthcare decisions. The second source of bias to consider is selective reporting of outcomes. Even if an RCT is published, can we be sure that the trialists really did what they said they would do when they set off on the long journey from trial protocol to published report? Although some changes may be inevitable, it is essential that any changes from the original plan (the trial protocol) are reported transparently, allowing others to make their own judgement of the possible impact of these changes on the trial’s validity. If a trial proposes to assess a number of outcomes, but only some are included in the final published report, is this because only the ‘positive’ outcomes were reported? Selective reporting of positive outcomes has been demonstrated in both the general medical and dermatology literature.8,10,11
So what can be done about this? BJD readers will be aware that trial registration has recently been debated in the European Parliament. After much pressure by groups such as the AllTrials campaign, Members of the European Parliament voted by a huge majority to adopt a new Clinical Trials Regulation from 2016.12,13 The new regulation will, among other things, require that all drug trials in Europe are registered before they begin [on the publicly accessible European Union (EU) Clinical Trials Register], and that a summary of the results from each trial is published on the register within a year of the trial’s end. Previous attempts to encourage clinical trial registration have lacked any ‘teeth’, but there are possible financial penalties for trialists who do not adhere to the new rules. While these will apply only to trials that have not yet started, it is certainly a positive step towards greater clinical trial transparency. Mandatory registration of all trials will help to reduce the impact of publication bias and selective reporting of outcomes. The next step will be to encourage full access to trial protocols as well.14
British Journal of Dermatology (2014) 171, pp681–683
681
682 Editorial
And what about randomized controlled trials published in the BJD? Although the BJD has supported the concept of trial registration since 2005,15 it has not insisted on mandatory trial registration in the manner of some high-impact journals.16 However, it would appear that the future direction of travel, in the EU at least, is towards mandatory registration of trials. While we acknowledge that the RCTs published in the BJD are often carried out in countries outside the EU, we believe that the positive impact of a policy of mandatory prospective trial registration (regardless of where the trials are carried out) merits adoption by the journal. Looking at recent submissions, trial registration is clearly not an alien concept to the authors submitting RCTs for publication to the BJD; approximately two-thirds of the RCTs submitted in the period of 2011–13 were registered. Although many of these were large RCTs produced with industry support (where familiarity with trial registration might be expected), many RCTs produced by independent researchers were also registered. However, due to the long timescales involved in designing and carrying out trials, it seems reasonable to allow an ‘amnesty’ period, after which trial registration will become mandatory for all RCTs submitted to the journal.
Which registry and when? We would expect all RCTs carried out in the EU to be registered on the EU Clinical Trials Register (www.clinicaltrials register.eu). RCTs carried out in any other country can be registered on any publicly accessible registry. Observational studies need not necessarily be registered but it is possible to do so. A large proportion of RCTs are registered on the Clinicaltrials.gov website (www.clinicaltrials.gov) or the Current Controlled Trials register (www.controlled-trials.com); this can be done free of charge or for a small fee. Many countries or regions have such registries already, such as the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) and the Netherlands Trial Register (www.trialregister.nl). The World Health Organization (WHO) has a list of primary registries in the WHO Registry Network (www.who.int/ictrp/ network/primary/en/), which meet specific criteria for content, quality and validity, accessibility, unique identification, technical capacity and administration. A registration number will be granted on registration; this can be included when the publication is sent to a scientific journal. The registry used by authors must be publicly accessible; internal registries that can be accessed only by specific employees of an organization are not acceptable. Stating other reference numbers, such as an ethical review board reference number (as has occurred with previous submissions to the BJD) is not an acceptable alternative. Registration must be prospective, not retrospective. This should be before any participants are recruited, although some registries do allow trials to be registered within a specified British Journal of Dermatology (2014) 171, pp681–683
time window after the first participant has been recruited. Registration of the trial after it has been completed (retrospective registration) is not acceptable. Authors of RCTs submitted to the BJD still sometimes give lack of awareness of trial registries as a reason for not registering their trial, but this no longer seems a reasonable excuse.
Protocols, interventions and outcome measures We would also like to draw trial authors’ attention to two other helpful resources: SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and TIDieR (Template for Intervention Description and Replication). The protocol of a clinical trial is essential for study conduct, review, reporting and interpretation. SPIRIT is an international initiative that aims to improve the quality of clinical trial protocols by defining an evidence-based set of items to address when preparing a protocol (www.spirit-statement.org). Once it has been prepared, the protocol should be made publicly available, either through publication or registration on a suitable registry. The quality of description of interventions in trial publications is often surprisingly poor. With a complete published description of interventions, clinicians and patients can reliably implement interventions that are shown to be useful, and other researchers can replicate or build on research findings. The TIDieR checklist and guide are useful resources to support the adequate description of trial interventions.17 A final point: there is considerable heterogeneity in the outcome measures (also called outcome domains or constructs) and outcome measurement instruments used in clinical trials. Recent efforts to harmonize outcome measures and instruments by developing core outcome sets (www.comet-initia tive.org; and for dermatology www.homeforeczema.org), and efforts to improve the quality of outcome measurement instruments (www.cosmin.nl) will lead to research of greater quality and validity. Trialists should be aware of these initiatives and should aim to include the recommended outcome measures in their trials.
A call to authors submitting clinical trial manuscripts to the BJD The WHO states that, ‘the registration of all interventional trials is a scientific, ethical and moral responsibility’. So, we encourage all authors planning to submit RCT reports to the BJD to register the trial prospectively and then report the trial clearly and transparently, following the CONSORT reporting guidelines. We also hereby give notice of an amnesty period, lasting until 1 October 2015, after which any RCT submitted to the BJD must be prospectively registered on a trial registry. We look forward to receiving and publishing many more high-quality, prospectively registered, transparently reported RCTs in the BJD in the coming years. © 2014 British Association of Dermatologists
Editorial
Conflicts of interest The authors are section editors for the British Journal of Dermatology, and coedit the ‘Putting Papers into Practice’ section of the journal. 1
Centre of Evidence Based Dermatology, King’s Meadow Campus, University of Nottingham, Lenton Lane, Nottingham, NG7 2NR, U.K. 2 Department of Dermatology, Academic Medical Center, University of Amsterdam, A0-227, PO Box 22700, 1100 DD, Amsterdam, The Netherlands E-mail: [email protected]
J. BATCHELOR1 P.I. SPULS2
References 1 Anstey A. The British Journal of Dermatology: 125 years, 28 editors, enduring values. Br J Dermatol 2013; 169:238. 2 Williams H. The outstanding record of clinical trials in the British Journal of Dermatology. Br J Dermatol 2014; 170:761–3. 3 Saurat JH, Stingl G, Dubertret L et al. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol 2008; 158:558–66. 4 Ruzicka T, Lynde CW, Jemec GB et al. Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebo-controlled, multicentre trial. Br J Dermatol 2008; 158:808–17.
© 2014 British Association of Dermatologists
683
5 Simes RJ. Publication bias: the case for an international registry of clinical trials. J Clin Oncol 1986; 4:1529–41. 6 Dickersin K, Rennie D. Registering clinical trials. JAMA 2003; 290:516–23. 7 Dwan K, Gamble C, Williamson PR et al. Systematic review of the empirical evidence of study publication bias and outcome reporting bias – an updated review. PLoS ONE 2013; 8:e66844. 8 Nankervis H, Baibergenova A, Williams HC, Thomas KS. Prospective registration and outcome-reporting bias in randomized controlled trials of eczema treatments: a systematic review. J Invest Dermatol 2012; 132:2727–34. 9 Chalmers I, Glasziou P. Avoidable waste in the production and reporting of research evidence. Lancet 2009; 374:86–9. 10 Mathieu S, Boutron I, Moher D et al. Comparison of registered and published primary outcomes in randomized controlled trials. JAMA 2009; 302:977–84. 11 Bourgeois FT, Murthy S, Mandl KD. Outcome reporting among drug trials registered in ClinicalTrials.gov. Ann Intern Med 2010; 153:158–66. 12 AllTrials. Europe votes for clinical trial transparency. Available at: http://www.alltrials.net/2014/europe-votes-for-clinical-trial-trans parency (last accessed 30 July 2014). 13 Goldacre B. Improving, and auditing, access to clinical trial results. BMJ 2014; 448:g213. 14 Chan A-W. Bias, spin, and misreporting: time for full access to trial protocols and results. PLoS Med 2008; 5:e230. 15 Ormerod AD, Williams HC. Compulsory registration of trials. Br J Dermatol 2005; 152:859–60. 16 Williams HC, Goldsmith L. The JID opens its doors to high quality randomised controlled clinical trials. J Invest Dermatol 2006; 126:1683–4. 17 Hoffman TC, Glasziou PP, Boutron I et al. Better reporting of interventions: template for intervention description and replication (TIDieR) checklist and guide. BMJ 2014; 348:g1687.
British Journal of Dermatology (2014) 171, pp681–683
